This invention relates to non-steroidal compounds that are modulators (i.e. agonists and antagonists) of androgen receptors, and to methods for the making and use of such compounds.
Intracellular receptors (IRs) form a class of structurally-related genetic regulators scientists have named xe2x80x9cligand dependent transcription factors.xe2x80x9d R. M. Evans, 240 Science, 889 (1988). Steroid receptors are a recognized subset of the IRs, including the progesterone receptor (PR), androgen receptor (AR), estrogen receptor (ER), glucocorticoid receptor (GR) and mineralocorticoid receptor (MR). Regulation of a gene by such factors requires both the IR itself and a corresponding ligand that has the ability to selectively bind to the IR in a way that affects gene transcription.
Ligands to the IRs can include low molecular weight native molecules, such as the hormones progesterone, estrogen and testosterone, as well as synthetic derivative compounds such as medroxyprogesterone acetate, diethylstilbesterol and 19-nortestosterone. These ligands, when present in the fluid surrounding a cell, pass through the outer cell membrane by passive diffusion and bind to specific IR proteins to create a ligand/receptor complex. This complex then translocates to the cell""s nucleus, where it binds to a specific gene or genes present in the cell""s DNA. Once bound to DNA, the complex modulates the production of the protein encoded by that gene. In this regard, a compound that binds an IR and mimics the effect of the native ligand is referred to as an xe2x80x9cagonistxe2x80x9d, while a compound that inhibits the effect of the native ligand is called an xe2x80x9cantagonist.xe2x80x9d
Ligands to the steroid receptors are known to play an important role in health of both women and men. For example, the native female ligand, progesterone, as well as synthetic analogues, such as norgestrel (18-homonorethisterone) and norethisterone (17xcex1-ethinyl-19-nortestosterone), are used in birth control formulations, typically in combination with the female hormone estrogen or synthetic estrogen analogues, as effective modulators of both PR and ER. On the other hand, antagonists to PR are potentially useful in treating chronic disorders, such as certain hormone dependent cancers of the breast, ovaries, and uterus, and in treating non-malignant conditions such as uterine fibroids and endometriosis, a leading cause of infertility in women. Similarly, AR antagonists, such as cyproterone acetate and flutamide have proved useful in the treatment of prostatic hyperplasia and cancer of the prostate.
The effectiveness of known modulators of steroid receptors is often tempered by their undesired side-effect profile, particularly during long-term administration. For example, the effectiveness of progesterone and estrogen agonists, such as norgestrel and diethylstilbesterol respectively, as female birth control agents must be weighed against the increased risk of breast cancer and heart disease to women taking such agents. Similarly, the progesterone antagonist, mifepristone (RU486), if administered for chronic indications, such as uterine fibroids, endometriosis and certain hormone-dependent cancers, could lead to homeostatic imbalances in a patient due to its inherent cross-reactivity as a GR antagonist. Accordingly, identification of compounds which have good specificity for one or more steroid receptors, but which have reduced or no cross-reactivity for other steroid or intracellular receptors, would be of significant value in the treatment of male and female hormone responsive diseases.
A group of quinoline analogs having an adjacent polynucleic ring system of the indene or fluorene series or an adjacent polynucleic heterocyclic ring system with substituents having a nonionic character have been described as photoconductive reducing agents, stabilizers, laser dyes and antioxidants. See e.g., U.S. Pat. Nos. 3,798,031; 3,830,647; 3,832,171; 3,928,686; 3,979,394; 4,943,502 and 5,147,844 as well as Soviet Patent No. 555,119; R. L. Atkins and D. E. Bliss, xe2x80x9cSubstituted Coumarins and Azacoumarins: Synthesis and Fluorescent Propertiesxe2x80x9d, 43 J. Org. Chem., 1975 (1978), E. R. Bissell et al., xe2x80x9cSynthesis and Chemistry of 7-Amino-4-(trifluoromethyl)coumarin and Its Amino Acid and Peptide Derivativesxe2x80x9d, 45 J. Org. Chem., 2283 (1980) and G. N. Gromova and K. B. Piotrovskii, xe2x80x9cRelative Volatility of Stabilizers for Polymer Materials,xe2x80x9d 43 Khim. Prom-st., 97 (Moscow, 1967). Further, a group of quinoline derivatives was recently described as modulators of steroid receptors. WO 96/19458, published Jun. 27, 1996.
The present invention is directed to compounds, pharmaceutical compositions, and methods for modulating processes mediated by androgen receptors (AR). More particularly, the invention relates to non-steroidal compounds and compositions which are high affinity, high specificity agonists, partial agonists (i.e., partial activators and/or tissue-specific activators) and antagonists for androgen receptors. Also provided are methods of making such compounds and pharmaceutical compositions, as well as critical intermediates used in their synthesis.
These and various other advantages and features of novelty that characterize the invention are pointed out with particularity in the claims annexed hereto and forming a part hereof. However, for a better understanding of the invention, its advantages, and objects obtained by its use, reference should be had to the accompanying descriptive matter, in which preferred embodiments of the invention are described.
As used herein, the following terms are defined with the following meanings, unless explicitly stated otherwise. Furthermore, in an effort to maintain consistency in the naming of compounds of similar structure but differing substituents, the compounds described herein are named according to the following general guidelines. The numbering system for the location of substituents on such compounds is also provided.
The term alkyl, alkenyl, alkynyl and allyl includes straight-chain, branched-chain, cyclic, saturated and/or unsaturated structures, and combinations thereof.
The term aryl refers to an optionally substituted six-membered aromatic ring, including polyaromatic rings and polycyclic ring systems of from two to four, more preferably two to three, and most preferably two rings.
The term heteroaryl refers to an optionally substituted five-membered heterocyclic ring containing one or more heteroatoms selected from the group consisting of carbon, oxygen, nitrogen and sulfur, including polycyclic rings of from two to four, more preferably two to three, and most preferably two rings, or a six-membered heterocyclic ring containing one or more heteroatoms selected from the group consisting of carbon and nitrogen, including polycyclic rings of from two to four, more preferably two to three, and most preferably two rings.
A 6a,10-dihydro-pyrrolidino[1,2a]quinoline is defined by the following structure. 
A 7a,11-dihydro-2-pyridono[5,6g]pyrrolidino[1,2a]quinoline is defined by the following structure. 
An 8-pyridono[5,6g]quinoline is defined by the following structure. 
A 9-pyridono[6,5i]julolidine is defined by the following structure. 
A 1,10-[1,3-dihydro-3-oxo-(2,1-isooxazolyl)]-8-pyridono[5,6g]quinoline is defined by the following structure. 
Compounds of the present invention are defined as those having the formula: 
wherein:
R1 is hydrogen, F, Cl, Br, I, NO2, OR20, NR21R22, SR20, a C1-C4 alkyl or perhaloalkyl, or is an optionally substituted allyl, arylmethyl, alkynyl, alkenyl, aryl or heteroaryl, where R21 is hydrogen, a C1-C6 alkyl or perfluoroalkyl, aryl, heteroaryl, optionally substituted allyl or arylmethyl, SO2R23 or S(O)R23, where R23 is hydrogen, a C1-C6 alkyl or perfluoroalkyl, aryl, heteroaryl, optionally substituted allyl or arylmethyl, R20 is hydrogen, a C1-C6 alkyl or perfluoroalkyl, aryl, heteroaryl, optionally substituted allyl or arylmethyl, and R22 is hydrogen, a C1-C4 alkyl or perfluoroalkyl, aryl, heteroaryl, optionally substituted allyl OR20 arylmethyl, OR or NHR21;
R2 is hydrogen, F, Br, Cl, a C1-C4 alkyl or perhaloalkyl, aryl, heteroaryl, CF3, CF2H, CFH2, CF2OR20, CH2OR20, or OR20, where R20 has the same definition given above;
R3 is hydrogen, a C1-C4 alkyl, F, Cl, Br, I, OR20, NR21R22 or SR20, where R20 through R22 have the definitions given above;
R4 and R5 each independently are hydrogen, a C1-C4 alkyl or perfluoroalkyl, heteroaryl, optionally substituted allyl, arylmethyl, alkynyl or alkenyl, or an aryl optionally substituted with hydrogen, F, Cl, Br, OR20 or NR21R22, or R4 and R5 taken together can form a three- to seven-membered ring optionally substituted with hydrogen, F, Cl, Br, OR20 or NR21R22, where R20 through R22 have the definitions given above;
R6 and R7 each independently are hydrogen, a C1-C4 alkyl or perfluoroalkyl, heteroaryl, optionally substituted allyl, arylmethyl, alkynyl or alkenyl, or an aryl optionally substituted with hydrogen, F, Cl, Br, OR20 or NR21R22, or R6 and R7 taken together can form a three- to seven-membered ring optionally substituted with hydrogen, F, Cl, Br, OR20 or NR21R22, where R20 through R22 have the definitions given above;
R8 is hydrogen, a C1-C12 alkyl or perfluoroalkyl, hydroxymethyl, aryl, heteroaryl or optionally substituted allyl, arylmethyl, alkynyl or alkenyl;
R9 through R18 each independently are hydrogen, a C1-C4 alkyl or perfluoroalkyl, heteroaryl, optionally substituted allyl, arylmethyl, alkynyl or alkenyl, or an aryl optionally substituted with hydrogen, F, Cl, Br, OR20 or NR21R22, or any two of R9 through R18 taken together can form a three- to seven-membered ring optionally substituted with hydrogen, F, Cl, Br, OR20 or NR21R22, where R20 through R22have the definitions given above;
R19 is F, NO2 or SR20, where R20 has the definition given above;
R24 is hydrogen, a C1-C4 alkyl, F, Cl, Br, I, NO2, OR20, NR21R22 or SR20, where R20 through R22 have the definitions given above;
R25 is hydrogen, a C1-C12 alkyl, or perfluoroalkyl, hydroxymethyl, aryl, heteroaryl or optionally substituted allyl, arylmethyl, alkynyl or alkenyl, or R25 and R8 taken together can form a three- to seven-membered ring optionally substituted with hydrogen, F, Cl, Br, OR20 or NR21R22, where R20 through R22have the definitions given above;
R26 is hydrogen, a C1-C6 alkyl or perfluoroalkyl, NO2, OR20, C(O)R20, C(O)OR20, C(O)NR21R22, or an optionally substituted aryl, heteroaryl, allyl or arylmethyl, where R20 through R22 have the definitions given above;
R27 and R28 each independently are hydrogen, F, Cl, Br, I, OR20, NR21R22, a C1-C4 alkyl or perfluoroalkyl, heteroaryl, optionally substituted allyl, arylmethyl, alkynyl or alkenyl, or an aryl optionally substituted with hydrogen, F, Cl, Br, OR20 or NR21R22, or R27 and R28 taken together can form a three- to seven-membered ring optionally substituted with hydrogen, F, Cl, Br, OR20 or NR21R22, where R20 through R22 have the definitions given above;
m is 0 or 1;
n is 0 or 1;
o is 0 or 1;
Y is O or S;
Z is O, S, NH, NR22 or NCOR22, where R22 has the sarne definition given above; and
any two of R4 through R8, R25 and R28 taken together can form a three- to seven-membered ring optionally substituted with hydrogen, F, Cl, Br, OR20 or NR21R22, where R20 through R22 have the definitions given above.
In a preferred aspect, the present invention provides a pharmaceutical composition comprising an effective amount of an androgen receptor modulating compound of formulae I through V shown above wherein R1 through R28, Y, Z, m, n and o all have the same definitions as given above.
In a further preferred aspect, the present invention comprises a method of modulating processes mediated by androgen receptors comprising administering to a patient an effective amount of a compound of the formulae I through V shown above, wherein R1 through R28, Y and Z all have the same definitions as those given above.
Any of the compounds of the present invention can be synthesized as pharmaceutically acceptable salts for incorporation into various pharmaceutical compositions. As used herein, pharmaceutically acceptable salts include, but are not limited to, hydrochloric, hydrobromic, hydroiodic, hydrofluoric, sulfuric, citric, maleic, acetic, lactic, nicotinic, succinic, oxalic, phosphoric, malonic, salicylic, phenylacetic, stearic, pyridine, ammonium, piperazine, diethylamine, nicotinamide, formic, urea, sodium, potassium, calcium, magnesium, zinc, lithium, cinnamic, methylamino, methanesulfonic, picric, tartaric, triethylamino, dimethylamino, and tris(hydroxymethyl)aminomethane. Additional pharmaceutically acceptable salts are known to those skilled in the art.
AR agonist, partial agonist and antagonist compounds of the present invention will prove useful in the treatment of acne, male-pattern baldness, male hormone replacement therapy, wasting diseases, hirsutism, stimulation of hematopoiesis, hypogonadism, prostatic hyperplasia, various hormone-dependent cancers, including, without limitation, prostate and breast cancer and as anabolic agents.
It will be understood by those skilled in the art that while the compounds of the present invention will typically be employed as a selective agonists, partial agonists or antagonists, that there may be instances where a compound with a mixed steroid receptor profile is preferred. For example, use of a PR agonist (i.e., progestin) in female contraception often leads to the undesired effects of increased water retention and acne flare-ups. In this instance, a compound that is primarily a PR agonist, but also displays some AR and MR modulating activity, may prove useful. Specifically, the mixed MR effects would be useful to control water balance in the body, while the AR effects would help to control any acne flare-ups that occur.
Furthermore, it will be understood by those skilled in the art that the compounds of the present invention, including pharmaceutical compositions and formulations containing these compounds, can be used in a wide variety of combination therapies to treat the conditions and diseases described above. Thus, the compounds of the present invention can be used in combination with other hormones and other therapies, including, without limitation, chemotherapeutic agents such as cytostatic and cytotoxic agents, immunological modifiers such as interferons, interleukins, growth hormones and other cytokines, hormone therapies, surgery and radiation therapy.
Representative AR modulator compounds (i.e., agonists and antagonists) according to the present invention include: (R/S)-6,7,7a,11-tetrahydro-7a-methyl-4-trifluoromethyl-2-pyridono[5,6-g]pyrrolidino[1,2-a]quinoline; (R/S)-3-fluoro-6,7,7a,11-tetrahydro-7a-methyl-4-trifluoromethyl-2-pyridono[5,6-g]pyrrolidino[1,2-a]quinoline; (R/S)-6,7,7a,11-tetrahydro-1,7a-dimethyl-4-trifluoromethyl-2-pyridono[5,6-g]pyrrolidino[1,2-a]quinoline; (R/S)-3-fluoro-6,7,7a,11-tetrahydro- 1,7a-dimethyl-4-trifluoromethyl-2-pyridono [5,6-g]pyrrolidino[1,2-a]quinoline; 11-(trifluoromethyl)-9-pyridono[6,5-i]julolidine; 8-methyl-11-(trifluoromethyl)-9-pyridono[6,5-i]julolidine; 7-fluoro- 1,2,3,4-tetrahydro-2,2-dimethyl-6-trifluoromethyl-8-pyridono[5,6-g]quinoline; 6-difluoromethyl-7-fluoro- 1,2,3,4-tetrahydro-2,2-dimethyl-8-pyridono[5,6-g]quinoline; 7-fluoro-1,2,3,4-tetrahydro-2,2,9-trimethyl-6-trifluoromethyl-8-pyridono[5,6-g]quinoline; 6-difluoromethyl-7-fluoro-1,2,3,4-tetrahydro-2,2,9-trimethyl-8-pyridono[5,6-g]quinoline; 7-fluoro-1,2,3,4-tetrahydro-1,2,2,9-tetramethyl-6-trifluoromethyl-8-pyridono[5,6-g]quinoline; 6-difluoromethyl-7-fluoro-1,2,3,4-tetrahydro-1,2,2,9-tetramethyl-8-pyridono[5,6-g]quinoline; 7-fluoro-1,2-dihydro-2,2,4-trimethyl-6-trifluoromethyl-8-pyridono[5,6-g]quinoline; 7-fluoro-1,2,3,4-tetrahydro-2,2,4-trimethyl-6-trifluoromethyl-8-pyridono[5,6-g]quinoline; 1,10-[1,3-dihydro-3-oxo-(2,1-isoxazolyl)]-1,2,3,4-tetrahydro-2,2,4,10-tetramethyl-6-trifluoromethyl-8-pyridono[5,6-g]quinoline; 7-fluoro-1,2-dihydro-2,2,4,10-tetramethyl-6-trifluoromethyl-8-pyridono[5,6-g]quinoline; 7-fluoro-1,2,3,4-tetrahydro-2,2,4,10-tetramethyl-6-trifluoromethyl-8-pyridono[5,6-g]quinoline; 7-fluoro-1,2,3,4-tetrahydro-2,2,4,9,10-pentamethyl-6-trifluoromethyl-8-pyridono[5,6-g]quinoline; 7-fluoro-1,2,3,4-tetrahydro-1,2,2,4,10-pentamethyl-6-trifluoromethyl-8-pyridono[5,6-g]quinoline; 1,2,3,4-tetrahydro-1-hydroxy-2,2-dimethyl-6-trifluoromethyl-8-pyridono[5,6-g]quinoline; 1,2,3,4-tetrahydro-1-hydroxy-2,2,9-trimethyl-6-trifluoromethyl-8-pyridono[5,6-g]quinoline; 2,2-diethyl-7-fluoro-1,2,3,4-tetrahydro-6-trifluoromethyl-8-pyridono[5,6-g]quinoline; (R/S)-4-ethyl-1-formyl-1,2,3,4-tetrahydro-6-(trifluoromethyl)-8-pyridono[5,6-g]quinoline; (R/S)-4-ethyl-1,2,3,4-tetrahydro-1-(trifluoroacetyl)-6-(trifluoromethyl)-8-pyridono[5,6-g]quinoline; (R/S)-1-acetyl-4-ethyl-1,2,3,4-tetrahydro-6-(trifluoromethyl)-8-pyridono[5,6-g]quinoline; (R/S)-4-ethyl-1,2,3,4-tetrahydro-10-nitro-6-(trifluoromethyl)-8-pyridono[5,6-g]quinoline; 1,2,3,4-tetrahydro-2,2-dimethyl-10-nitro-6-(trifluoromethyl)-8-pyridono[5,6-g]quinoline; 1,2,3,4-tetrahydro-2,2-dimethyl-7,10-dinitro-6-(trifluoromethyl)-8-pyridono[5,6-g]quinoline; and (R/S)-4-ethyl-1,2,3,4-tetrahydro-1-nitro-6-(trifluoromethyl)-8-pyridono[5,6-g]quinoline.
Compounds of the present invention, comprising classes of heterocyclic nitrogen compounds and their derivatives, that can be obtained by routine chemical synthesis by those skilled in the art, e.g., by modification of the heterocyclic nitrogen compounds disclosed or by a total synthesis approach.
The sequences of steps for several general schemes to synthesize the compounds of the present invention are shown below. In each of the Schemes the R groups (e.g., R1, R2, etc.) correspond to the specific substitution patterns noted in the Examples. However, it will be understood by those skilled in the art that other functionalities disclosed herein at the indicated positions of compounds of formulas I through V also comprise potential substituents for the analogous positions on the structures within the Schemes. 
The process of Scheme I begins with an acetylide addition to 5-chloro-2-pentanone (Compound 1) with, for example, ethynylmagnesium bromide. The alcohol is then esterified to the corresponding acetate (Compound 2) with, for example, acetic anhydride and 4-dimethylaminopyridine in pyridine. A tandem propargylation/alkylation of Compound 2 with aniline (Compound 3) in the presence of a copper (I) or copper (II) salt, such as copper(I) chloride, and a base, such as triethylamine, affords Compound 4. See Y. Imada, M. Yuasa, I. Nakamura and S.-I. Murahashi, xe2x80x9cCopper(I)-Catalyzed Amination of Propargyl Esters. Selective Synthesis of Propargylamines, 1-Alken-3-ylamines, and (Z)-Allylamines.xe2x80x9d, J. Org. Chem. 1994, 59, 2282, the disclosure of which is herein incorporated by reference. Cyclization of Compound 4 occurs in the presence of a copper catalyst, such as copper(I) chloride, to afford Compound 5. See N. R. Easton and D. R. Cassady, xe2x80x9cA Novel Synthesis of Quinolines and Dihydroquinolines.xe2x80x9d J. Org. Chem. 1962, 27, 4713, and N. R. Easton and G. F. Hennion, xe2x80x9cMetal Catalyst Process for Converting xcex1-Amino-Acetylenes to Dihydroquinolinexe2x80x9d, U.S. Pat. No. 3,331,846 (1967), the disclosure of which is herein incorporated by reference.
Reduction of the olefin with, for example, hydrogen over a metal catalyst such as palladium on carbon, affords Compound 6. Nitration of Compound 6 with, for example, fuming nitric acid, followed by reduction of the nitro group with, for example, hydrogen over a metal catalyst such as palladium on carbon, affords the desired diamine (Compound 7A) along with small amounts of a regioisomer, which was separated (Compound 7B). A Knorr cyclization of Compound 7A with a xcex2-keto ester or hydrated derivative, effected by, for example, zinc chloride, affords a compound of structure 8. See: E. T. McBee, O. R. Pierce, H. W. Kilbourne, and E. R. Wilson, xe2x80x9cThe Preparation and Reactions of Fluorine-containing Acetoacetic Esters.xe2x80x9d J. Am. Chem. Soc. 1953, 75, 3152, the disclosure of which is herein incorporated by reference, for the preparation of the fluorinated acetoacetate reagents. A compound of structure 8 may be further transformed into a compound of structure 9 by treatment of structure 8 with a base, such as sodium hydride, and an alkylating agent, such as methyl iodide. 
The process of Scheme II begins with the nitration of a tricyclic tetrahydroquinoline such as julolidine, Compound 10, followed by reduction of the nitro group to afford an aniline such as Compound 11. Treatment of Compound 11 with a xcex2-keto ester such as ethyl 4,4,4-trifluoroacetoacetate and a Lewis acid such as zinc chloride (the Knorr reaction) affords a tetracyclic quinolinone such as Compound 12. The quinoline may be further functionalized by alkylation of the amide nitrogen by, for example, treatment with a base such as sodium hydride followed by the addition of an alkylating agent such as iodomethane, to afford a compound like Compound 13. 
The process of Scheme III begins with an esterification of a propargyl alcohol (structure 14) with, for example, acetic anhydride and 4-dimethylaminopyridine in pyridine (structure 15). Alkylation of the acetate with aniline (Compound 3) in the presence of a copper(I) or copper(II) salt, such as copper(I) chloride, and a base, such as triethylamine affords a compound of structure 16. Cyclization of structure 16 occurs in the presence of a copper catalyst, such as copper(I) chloride, to afford a compound of structure 17.
Reduction of the olefin, with for example, hydrogen over a metal catalyst, such as palladium on carbon, affords a compound of structure 18. Nitration of a compound of structure 18 with, for example, fuming nitric acid, followed by reduction of the nitro group, with, for example hydrogen over a metal catalyst such as palladium on carbon, affords a compound of DOCKET NO. structure 19. A Knorr cyclization of a compound of structure 19 with a xcex2-keto ester or hydrated derivative, effected by, for example, zinc chloride, affords a compound of structure 20. A compound of structure 20 may be further transformed into a compound of structure 21 by treatment of structure 20 with a base, such as sodium hydride, and an alkylating agent, such as methyl iodide. A compound of structure 21 may be further transformed by reductive alkylation with, for example, paraformaldehyde and sodium borohydride in acetic acid, to afford a compound of structure 22. 
The process of Scheme IV begins with the acylation of a 3-nitroaniline (structure 23) with an acylating agent, for example, di-tert-butyl dicarbonate or trimethylacetyl chloride, to afford a compound of structure 24. Reduction of the nitro group with, for example, hydrogen over a metal catalyst such as palladium on carbon, affords the corresponding aniline (structure 25). Treatment of a compound of structure 25 with acetone and a catalyst such as iodine affords a compound of structure 26, in a process known as the Skraup cyclization. See R. H. F. Manske and M. Kulka, xe2x80x9cThe Skraup Synthesis of Quinolinesxe2x80x9d, Organic Reactions 1953, 7, 59, the disclosure of which is herein incorporated by reference. Deprotection by either acid or base, followed by treatment of the corresponding aniline with a xcex2-keto ester (or corresponding hydrate) in the presence of a Lewis acid such as zinc chloride, affords as the major product a compound of structure 27. The cyclization of an aniline as described above is known as a Knorr cylization. See G. Jones, xe2x80x9cPyridines and their Benzo Derivatives: (v) Synthesisxe2x80x9d. In Comprehensive Heterocyclic Chemistry, Katritzky, A. R.; Rees, C. W., eds. Pergamon, New York, 1984. Vol. 2, chap. 2.08, pp 421-426. In turn, the quinolinone nitrogen may be alkylated by, for example, treatment with sodium hydride followed by iodomethane, to afford a compound of structure 28. Likewise, the quinoline nitrogen may be alkylated by, for example, treatment with paraformaldehdye and sodium cyano borohydride, to afford a compound of structure 29. 
The process of Scheme V involves the reduction of the C(3)-C(4) olefin of a compound of structure 27 to afford a tetrahydroquinoline of structure 30, which may be accomplished by a hydrogenation with, for example, hydrogen over palladium on carbon, or by a cationic process with, for example, trifluoroacetic acid and triethylsilane. 
The process of Scheme VI involves the oxidation of both the quinoline nitrogen and C(10) alkyl group of a compound of structure 30, followed cyclization and loss of water to afford a compound of structure 31. This may be effected by treatment of a compound of structure 30 (R1=alkyl, preferably methyl) with an oxygen transfer agent or combination of oxygen transfer agents, such as hydrogen peroxide in the presence of peracetic acid, to afford a (Y compound of structure 31. 
The process of Scheme VII involves the alkyation of one or both of the nitrogen atoms of a compound of structure 30. The quinolinone nitrogen may be selectively alkylated by treatment with a base, such as sodium hydride, followed by an alkylating agent, such as methyl iodide, to afford a compond of structure 32. The quinoline nitrogen may be selectively alkylated by a reductive alkylation procedure using, for example, paraformaldehdye in the presence of sodium cyano borohydride and acetic acid, to afford a compound of structure 33. Subsequently, the quinoline nitrogen of a compound of structure 32 may be reductively alkylated in a manner similar to the conversion of 30 to 33, or the quinolinone nitrogen of a compound of structure 33 may be alkylated in a manner similar to the conversion of 30 to 32. Either of these processes will afford a compound of structure 34. 
The process of Scheme VIII begins with the oxidation of the quinoline nitrogen atom of a compound of structure 20 with an oxygen transfer agent or mixture of oxygen transfer agents, for example, hydrogen peroxide in the presence of peracetic acid, to afford a compound of structure 35. The quinolinone nitrogen may subsequently be alkylated by, for example, treatment with sodium hydride and methyl iodide, to afford a compound of structure 36. 
The process of Scheme IX begins with the reaction of an aniline (structure 37) with an unsaturated acid, for example acrylic acid, followed by a cyclization reaction mediated by, for example, polyphosphoric acid to afford a 4-quinolinone. The nitrogen atom is then protected by treatment with a base, for example, 4-dimethylaminopyridine, followed by the addition of an acylating agent such as di-tert-butyldicarbonate, to afford a compound of structure 38. Addition of an organomagnesium or organolithium reagent, with, for example, ethyl magnesium bromide, affords an alcohol. Reduction of the alcohol with, for example hydrogen over palladium on carbon, followed by deprotection of the nitrogen atom, affords a compound of structure 39. Nitration of a compound of structure 39 by the action of nitric acid in the presence of, for example, sulfuric acid, followed by reduction of the nitro group with, for example, hydrogen over palladium on carbon, affords a 7-amino-1,2,3,4-tetrahydroquinoline of structure 40. A Knorr cyclization with a xcex2-keto ester effected by, for example, zinc chloride, affords a compound of structure 41. A compound of structure 41 may be further transformed into a compound of structure 42 by acylation of the quinoline nitrogen, which may be accomplished in one of two ways. Treatment of structure 41 with an acid chloride, for example, acetyl chloride, followed by treatment with a base, for example, potassium carbonate, to afford a compound of structure 42. Alternatively, treatment of structure 41 may be treated with an anhydride, for example, trifluoroacetic anhyride, likewise to afford a compound of structure 42. 
The process of Scheme X involves the treatment of structure 43 with, for example, nitric acid in the presence of, for example, sulfuric acid, to afford compounds of structure 44, 45 and 46.
The compounds of the present invention also include racemates, stereoisomers and mixtures of said compounds, including isotopically-labeled and radio-labeled compounds. Such isomers can be isolated by standard resolution techniques, including fractional crystallization and chiral column chromatography.
As noted above, any of the steroid modulator compounds of the present invention can be combined in a mixture with a pharmaceutically acceptable carrier to provide pharmaceutical compositions useful for treating the biological conditions or disorders noted herein in mammalian, and more preferably, in human patients. The particular carrier employed in these pharmaceutical compositions may take a wide variety of forms depending upon the type of administration desired, e.g., intravenous, oral, topical, suppository or parenteral.
In preparing the compositions in oral liquid dosage forms (e.g., suspensions, elixirs and solutions), typical pharmaceutical media, such as water, glycols, oils, alcohols, flavoring agents, preservatives, coloring agents and the like can be employed. Similarly, when preparing oral solid dosage forms (e.g., powders, tablets and capsules), carriers such as starches, sugars, diluents, granulating agents, lubricants, binders, disintegrating agents and the like will be employed. Due to their ease of administration, tablets and capsules represent the most advantageous oral dosage form for the pharmaceutical compositions of the present invention.
For parenteral administration, the carrier will typically comprise sterile water, although other ingredients that aid in solubility or serve as preservatives may also be included. Furthermore, injectable suspensions may also be prepared, in which case appropriate liquid carriers, suspending agents and the like will be employed.
For topical administration, the compounds of the present invention may be formulated using bland, moisturizing bases, such as ointments or creams. Examples of suitable ointment bases are petrolatum, petrolatum plus volatile silicones, lanolin, and water in oil emulsions such as Eucerin(trademark) (Beiersdorf). Examples of suitable cream bases are Nivea(trademark) Cream (Beiersdorf), cold cream (USP), Purpose Cream(trademark) (Johnson and Johnson), hydrophilic ointment (USP), and Lubriderm(trademark) (Warner-Lambert).
The pharmaceutical compositions and compounds of the present invention will generally be administered in the form of a dosage unit (e.g., tablet, capsule etc.) at from about 1 xcexcg/kg of body weight to about 500 mg/kg of body weight, more preferably from about 10 xcexcg/kg to about 250 mg/kg, and most preferably from about 20 xcexcg/kg to about 100 mg/kg. As recognized by those skilled in the art, the particular quantity of pharmaceutical composition according to the present invention administered to a patient will depend upon a number of factors, including, without limitation, the biological activity desired, the condition of the patient, and tolerance for the drug.
The compounds of this invention also have utility when radio- or isotopically-labeled as ligands for use in assays to determine the presence of AR in a cell background or extract. They are particularly useful due to their ability to selectively activate androgen receptors, and can therefore be used to determine the presence of such receptors in the presence of other steroid receptors or related intracellular receptors.
Due to the selective specificity of the compounds of this invention for steroid receptors, these compounds can be used to purify samples of steroid receptors in vitro. Such purification can be carried out by mixing samples containing steroid receptors with one or more of the compounds of the present invention so that the compounds bind to the receptors of choice, and then separating out the bound ligand/receptor combination by separation techniques that are known to those of skill in the art. These techniques include column separation, filtration, centrifugation, tagging and physical separation, and antibody complexing, among others.
The compounds and pharmaceutical compositions of the present invention can advantageously be used in the treatment of the diseases and conditions described herein. In this regard, the compounds and compositions of the present invention will prove particularly useful as modulators of male sex steroid-dependent diseases and conditions such as the treatment of acne, male-pattern baldness, male hormone replacement therapy, wasting diseases, hirsutism, stimulation of hematopoiesis, hypogonadism, prostatic hyperplasia, various hormone-dependent cancers, including, without limitation, prostate and breast cancer and as anabolic agents.
The compounds and pharmaceutical compositions of the present invention possess a number of advantages over previously identified steroidal and non-steroidal compounds.
Furthermore, the compounds and pharmaceutical compositions of the present invention possess a number of advantages over previously identified steroid modulator compounds. For example, the compounds are extremely potent activators AR, preferably displaying 50% maximal activation of AR at a concentration of less than 100 nM, more preferably at a concentration of less than 50 nM, more preferably yet at a concentration of less than 20 nM, and most preferably at a concentration of 10 nM or less. Also, the selective compounds of the present invention generally do not display undesired cross-reactivity with other steroid receptors, as is seen with the compound mifepristone (RU486; Roussel Uclaf), a known PR antagonist that displays an undesirable cross reactivity on GR and AR, thereby limiting its use in long-term, chronic administration. In addition, the compounds of the present invention, as small organic molecules, are easier to synthesize, provide greater stability and can be more easily administered in oral dosage forms than other known steroidal compounds.